Information Integration

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Very little happens anywhere in the human body without the brain playing a part by monitoring the situation and exerting its influence. The brain can thus be expected to have a critical role in regulating weight through its direction of appetite, motivation and physical activity, as well as its management of how energy is allocated within the body.

Indeed, a small region at the base of the brain called the hypothalamus has been known for many years to be central to these energy-regulating activities. In animal studies, placing tiny lesions in this area can cause obesity or leanness depending on their precise location. Such observations have led to certain parts of the hypothalamus being labeled as "satiety" or "feeding" centers.

By stimulating appetite or the feeling of satiety, the brain can directly manage the body's energy balance from day to day. Over longer periods, signaling from the brain can also suppress nonessential systems, such as growth and reproduction, when fat stores are too low and energy must be conserved for survival. For the brain to command any of these mechanisms in response to the body's needs, however, it must receive updated information about how much stored energy is available.

What might this signal be, and how might it work? Many different molecules have been shown to influence appetite as their levels in the bloodstream rise and fall, including various breakdown products of food, such as glucose, and gut-derived hormones, such as insulin and cholecystokinin (CCK). But a critical regulator of how much energy is maintained in storage proved elusive until Jeffrey Friedman of the Rockefeller University and his colleagues discovered leptin in 1994.

Decades earlier a spontaneous syndrome of severe obesity with increased appetite and decreased energy expenditure appeared in certain mice bred at the Jackson Laboratory in Maine. Because a mouse had to inherit the trait from both parents, the syndrome itself was called ob/ ob. Despite hundreds of studies attempting to understand obesity in these mice, Friedman's group was the first to identify the inherited gene mutation responsible. The researchers also determined that the newly identified gene was predominantly active in fat cells and gave rise to a protein that was not made in functional form in the mice harboring the ob mutation. The obesity syndrome seemed to be caused by the absence of this substance.

The researchers named the protein leptin, from the Greek root leptos, for "thin," and quickly demonstrated that replacing the missing leptin by daily injections lowered the weight of affected mice by reducing their appetite and increasing their energy expenditure. Very soon, others furthered this remarkable discovery by finding a similar loss-of-function mutation in the human leptin gene among people with extremely rare cases of severe, early-onset obesity. Administering leptin to these subjects helped them to lose weight just as it had the mice.

These experiments demonstrated for the first time a physiological system whereby fat cells produce a hormonal signal that reflects their state of energy storage--the more triglyceride a fat cell contains, the more leptin it generates--and to which the brain responds by altering appetite and energy expenditure. When this energy-status signal is absent, either because the genetic mutation prevents functional leptin proteins from being manufactured or because the body actually has low fat stores, the brain believes that the body is starving and behaves accordingly by promoting hunger and energy conservation.

The discovery of leptin opened the door to exploration of a whole new biological pathway of cellular signaling and responses. The brain was clearly a major target of leptin secreted into the bloodstream by fat cells, and researchers, including ourselves, have begun to learn many of the detailed neural circuits and cell types through which leptin acts. As might be expected, many of them are in the hypothalamus.

In a structure called the arcuate nucleus of the hypothalamus, within the area previously identified as a satiety center, leptin simultaneously affects two neighboring neuron populations that control appetite in opposite ways. One set of neural cells produces a peptide called alpha-MSH that reduces appetite and, consequently, body weight. The other set of neurons produces two neuropeptides, NPY and AgRP, both of which stimulate feeding and promote obesity. Leptin's interactions with both these cell groups are quite elegant. Neurons that produce MSH connect to neurons elsewhere in the hypothalamus that carry a surface protein known as the melanocortin 4 receptor (MC4R), whose activation reduces appetite and promotes weight loss. AgRP, the peptide that promotes feeding, is an antagonist of this receptor, meaning that it prevents receptor activation. Thus, leptin acts to trigger MC4 receptors both by stimulating them directly via the MSH-producing neurons and by inhibiting their antagonist.

At the same time, leptin also affects the brain area previously viewed as a feeding center, the lateral hypothalamus, in an interesting way. One group of cells in that region produces a small protein called melanin-concentrating hormone (MCH). In 1996 our research group discovered that levels of this peptide are raised in the ob/ob mouse type, suggesting that leptin normally inhibits production of the peptide. We also established that increased MCH promotes food intake and obesity and found that even ob/ ob mice, if they lack the ability to manufacture MCH, are substantially less obese. We had thus found another clear example of the physiological system through which leptin acts as a signal that regulates hypothalamic neuropeptides, which in turn exert control over appetite and energy balance.

The same cells and circuits affected by leptin, moreover, are also acted on by numerous other circulating factors. The hypothalamus and related brain areas integrate all this information coming from diverse sources to produce a real-time picture of the body's energy status and orchestrate responses to manage energy resources. For a better understanding of what these signals, including leptin, are telling the brain, researchers are also studying how and where they originate.